Potassium Carbonate → Ethyl 6-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)picolinate

HRID 2356612

Reaktionsgleichung

Reaktionsgleichung von HRID 2356612
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])=[C:6](B(O)O)[CH:7]=1.Cl.Cl[CH2:23][C:24]1[N:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>O.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH2:23][C:24]2[N:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[CH:26][CH:25]=2)[CH:7]=1

Komponenten

6

Edukt 4

HCID 11430Potassium CarbonateHCID 21863594Toluene ethanolHCID 59384250HCID 59384250, VerbindungHCID 68457584Ethyl 6-(chloromethyl)picolinate hydrochloride

Produkt 1

HCID 59384237Ethyl 6-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)picolinateAusbeute 42,5 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 21584184Diethylether waterLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

A mixture of 78.56 g (249.4 mmol) of (5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)boronic acid, 59.9 g (249.4 mol) of ethyl 6-(chloromethyl)-2-pyridinecarboxylate hydrochloride, 137.68 g (997.7 mol) of potassium carbonate and 28.89 g (24.95 mmol) of tetrakis(triphenylphoshine)palladium(0) in 1:1 toluene/ethanol (1840 ml) was stirred and heated at 90° C. under argon for 2 hours. Cooled, diluted with water/ether and filtered. Organic phase was washed with 2M hydrochloric acid and water, dried overnight (sodium sulphate), filtered and evaporated. Dissolved in dichloromethane, filtered to remove some insoluble material and the filtrate applied to a large column on the Biotage 75 and eluted with 15% ethyl acetate in hexane. Some purification but lower spot started to elute with product so eluent changed to ethyl acetate/hexane (1:1) and all fractions containing product combined and evaporated. Redissolved in dichloromethane and biotaged (chromatographed) again on same size column eluting with 4 litres of (3:1) dichloromethane/hexane changing to 5% ethanol in dichloromethane to remove the remaining product. Evaporated in vacuo and recrystallised from ethanol (1 litre) cooling to 20° C. in an ice bath then filtering off immediately to give 46 g of product. MLS (mother liquors) were left over the weekend when more solid separated which was filtered off but TLC showed this to be impurity and leaving very of this in the filtrate. MLS evaporated and recrystallised from ethanol (140 ml) to give 9.4 g of product. NMR and LC/MS of both products identical. (total yield of 55.4 g).

Aufarbeitung

  1. temperatureCooled
  2. filtrationfiltered
  3. washOrganic phase was washed with 2M hydrochloric acid and water
  4. dry with materialdried overnight (sodium sulphate)
  5. filtrationfiltered
  6. customevaporated
  7. dissolutionDissolved in dichloromethane
  8. filtrationfiltered
  9. customto remove some insoluble material
  10. washeluted with 15% ethyl acetate in hexane
  11. customSome purification but lower spot
  12. washto elute with product so eluent
  13. additionall fractions containing product
  14. customevaporated
  15. dissolutionRedissolved in dichloromethane
  16. custombiotaged (chromatographed) again on same size column
  17. washeluting with 4 litres of (3:1) dichloromethane/hexane changing to 5% ethanol in dichloromethane
  18. customto remove the remaining product
  19. customEvaporated in vacuo
  20. customrecrystallised from ethanol (1 litre)
  21. temperaturecooling to 20° C. in an ice bath
  22. filtrationthen filtering off immediately

Quellen und Nachweise

ORD-Eintrag
ord-7dfd0f3486ad4deabc97590816f979f8
Quelldatensatz
uspto-grants-2010_07
Patentnummer
US07759369B2

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